Effect of genetic polymorphisms of CYP3A5 and MDR1 on cyclosporine concentration during the early stage after renal transplantation in Chinese patients co-treated with diltiazem.
OBJECTIVE
The aim of this study was to assess the influence of the cytochrome (CYP450)3A5 and multidrug resistance (MDR1) gene polymorphisms on cyclosporine A (CsA) trough concentration during the early stage after renal transplantation in Chinese patients co-treated with diltiazem.


METHODS
CYP3A5*3 (A6986G) and MDR1 C1236T, G2677T/A and C3435T polymorphisms were determined by PCR followed by restriction fragment length polymorphism (RFLP) analysis. A total of 112 Chinese renal transplant patients were enrolled in the study. The whole blood trough concentration was measured at 7 days after transplantation, and the dose-adjusted trough levels were compared among the different genotypes.


RESULTS
The dose-adjusted trough levels of CsA were significantly higher in MDR1 2677TT carriers than in GG plus GT carriers (59.5 +/- 15.9 vs. 34.5 +/- 9.4 vs. 43.2 +/- 13.6 ng/mL per mg per kg; P < 0.0001). In patients who were co-treated with diltiazem, compared with carriers of haplotype T-T-C, the carriers of haplotype C-G-C and haplotype T-G-T had significantly lower dose-adjusted trough blood concentrations of CsA than the non-carrier group (P = 0.002, P = 0.000 and P = 0.000, respectively). However, no evidence was found that there was a relationship between the CYP3A5*3, MDR1 C1236T and MDR1 C3435T polymorphisms and CsA dose-adjusted trough concentrations.


CONCLUSIONS
This study demonstrated that the G2677T/A single nucleotide polymorphisms in MDR1 and MDR1 haplotypes C-G-C, T-G-T and T-T-C are associated with the CsA concentration during the very early post-transplant period in Chinese renal transplant patients co-treated with diltiazem. These polymorphisms may be useful for determining the appropriate initial dose of CsA after renal transplantation.
Wang
Yixi
Y
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
Wang
Changxi
C
Li
Jiali
J
Wang
Xueding
X
Zhu
Genglong
G
Chen
Xiao
X
Bi
Huichang
H
Huang
Min
M
D000328:Adult; D000368:Aged; D044466:Asian People; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004110:Diltiazem / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic; D013997:Time Factors; D055815:Young Adult
D002121:Calcium Channel Blockers; D016572:Cyclosporine; D051544:Cytochrome P-450 CYP3A; D004110:Diltiazem; D007166:Immunosuppressive Agents; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C510164:CYP3A5 protein, human; C421109:multidrug resistance-associated protein 1